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Published online before print July 6, 2004
Protein Science, DOI: 10.1110/ps.04773204
 Copyright © 2004 The Protein Society
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A mobile loop order–disorder transition modulates the speed of chaperonin cycling

Frank Shewmaker1,2, Michael J. Kerner3, Manajit Hayer-Hartl3, Gracjana Klein2, Costa Georgopoulos2 and Samuel J. Landry1

1 Department of Biochemistry, Tulane University Health Sciences Center, New Orleans, Louisiana 70112, USA
2 Département de Biochimie Médicale, University of Geneva, 1211 Geneva, Switzerland
3 Max-Planck-Institut für Biochemie, Department of Cellular Biochemistry, D-82152 Martinsried, Germany

(RECEIVED March 26, 2004; FINAL REVISION May 4, 2004; ACCEPTED May 4, 2004)

Molecular machines order and disorder polypeptides as they form and dissolve large intermolecular interfaces, but the biological significance of coupled ordering and binding has been established in few, if any, macromolecular systems. The ordering and binding of GroES co-chaperonin mobile loops accompany an ATP-dependent conformational change in the GroEL chaperonin that promotes client protein folding. Following ATP hydrolysis, disordering of the mobile loops accompanies co-chaperonin dissociation, reversal of the GroEL conformational change, and release of the client protein. "High-affinity" GroEL mutants were identified by their compatibility with "low-affinity" co-chaperonin mutants and incompatibility with high-affinity co-chaperonin mutants. Analysis of binding kinetics using the intrinsic fluorescence of tryptophan-containing co-chaperonin variants revealed that excessive affinity causes the chaperonin to stall in a conformation that forms in the presence of ATP. Destabilizing the {beta}-hairpins formed by the mobile loops restores the normal rate of dissociation. Thus, the free energy of mobile-loop ordering and disordering acts like the inertia of an engine’s flywheel by modulating the speed of chaperonin conformational changes.

Keywords: nuclear magnetic resonance; surface plasmon resonance; ATP hydrolysis; folding funnel; allele-specific genetic interaction; intrinsically unstructured protein

Reprint requests to: Samuel J. Landry, Department of Biochemistry SL43, 1430 Tulane Avenue, New Orleans, LA 70112, USA; e-mail: landry{at}tulane.edu; fax: (504) 584-2739.

Supplemental material: see www.proteinscience.org

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.04773204.


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